US8063043B2 - Salts of N-[6-cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide - Google Patents

Salts of N-[6-cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide Download PDF

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US8063043B2
US8063043B2 US13/061,572 US200913061572A US8063043B2 US 8063043 B2 US8063043 B2 US 8063043B2 US 200913061572 A US200913061572 A US 200913061572A US 8063043 B2 US8063043 B2 US 8063043B2
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methyl
trifluoromethoxy
biphenyl
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Joginder Bajwa
Marilyn De La Cruz
Stephanie Kay Dodd
Liladhar Murlidhar Waykole
Raeann Wu
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Sun Pharma Global FZE
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide are prepared and characterized.

Description

This is a National Stage of International Application No. PCT/US2009/056918 filed on Sep. 15, 2009, which claims benefit of U.S. Provisional Application No. 61/097,580 filed Sep. 17, 2008, which in its entirety are herein incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide, as well as to pharmaceutical compositions comprising the same and methods of treatment using the same.
2. Related Background Art
The compound N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide has the formula (I):
Figure US08063043-20111122-C00001

as described in WO 2007/131201. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as modulating the activity of the hedgehog signaling pathway useful in therapy for diseases which respond to modulating the activity of the hedgehog signaling pathway. WO 2007/131201 does not disclose any specific salts or salt hydrates or solvates of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide.
It has been found that the salt forms of the present invention shows that in addition to good physico-chemical properties that salts may have high permeability and high bioavailability.
SUMMARY OF THE INVENTION
The present invention is directed to salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide. Preferred embodiments of the present invention are directed to the hydrochloride, diphosphate and sulfate salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide.
The invention is further directed to pharmaceutical compositions comprising:
  • (a) a therapeutically effective amount of an inventive salt of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide; and
  • (b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.
The present invention is also directed to a method of treating a disease which responds to modulating the activity of the hedgehog signaling pathway comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of an inventive salt of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide diphosphate salt.
FIG. 2 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide monosulfate salt.
FIG. 3 shows the x-ray powder diffraction pattern for N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide monohydrochloride salt.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “salt” refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; as used herein, “salt” includes hydrates and solvates of salts made in accordance with this invention. Exemplary pharmaceutically acceptable mineral or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P. H. Stahl and C. G. Wermuth (eds.), VHCA, Zurich 2002, pp. 334-345. In particular, salts include, but are not limited to, hydrochloride, phosphate, sulfate, mesylate, esylate and besylate salt forms. As used herein, “polymorph” refers to a distinct “crystal modification” or “polymorphic form” or “crystalline form”, which differs from another with respect to x-ray powder diffraction pattern, physico-chemical and/or pharmacokinetic properties, and thermodynamic stability.
An embodiment of the present invention is directed to salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide. In preferred embodiments, the salt is selected from the mono hydrochloride, diphosphate and mono sulfate salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide. A particularly preferred embodiment of the of the present invention are the diphosphate and the mono sulfate salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide.
The present invention may be used for treating carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine and endocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, medulloblastoma and schwannomas; tumors of mesenchymal origin including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors including melanoma, Merkel cell carcinoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma. The present invention may also be used for treating mastocytosis, germ cell tumors, pediatric sarcomas, and other cancers.
The present invention is also useful for inhibiting the growth and proliferation of hematopoietic tumors of lymphoid lineage such as leukemia, including acute lymphocytic leukemia (ALL), acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkitts lymphoma; and hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias (CML), myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia.
EXAMPLE 1 Preparation of the Diphosphate Salt
To a 250 mL, three-necked reaction flask 7.0 g (0.0144 mole) of 2-methyl-4′-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide free base and acetonitrile (178.5 mL, HPLC grade) was added under nitrogen. The suspension was heated to 58° C. under nitrogen over 20 minutes to obtain a clear solution. To the reaction solution 3.403 g of 85% phosphoric acid in water (2 equiv) was added over 18 minutes. Within 5 minutes of the phosphoric acid addition, N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide di-phosphate precipitates out. The white slurry was stirred and cooled to room temp over 100 minutes. The slurry was then cooled to 0±5° C. over 5 minutes and stirred for 1 hour. The mixture was filtered under suction and solid was washed with acetonitrile (3×9.4 mL). The drug substance was dried under vacuum at 50° C. for 16 hours to obtain 9.63 g of the phosphate salt (yield: 98%).
EXAMPLE 2 Preparation for the Monosulfate Salt
To a 100 mL, three-necked reaction flask was charged 3.0 g (6.18 mmole) of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide free base and acetonitrile (35 mL, HPLC grade) under nitrogen. The suspension was heated to 50° C. under nitrogen over 30 minutes to obtain a clear solution. To the mixture was added a 1.5 mL of 6 M sulfuric acid (1.5 equiv) over 10 minutes. The mixture was stirred at 50° C. for 3 hours and allowed to cool to 25° C. over 25 minutes. Within 5 minutes the solids came out. The slurry was stirred at 25° C. for 16 hours. The mixture was filtered under suction and solid was washed with acetonitrile (10 mL). The drug substance was dried under vacuum at 55° C. for 16 hours to obtain 3.0 g of the sulfate salt (yield: 83%).
EXAMPLE 3 Preparation for the Monohydrochloride Salt
To a 100 mL, three-necked reaction flask was charged 3.0 g (6.18 mmole) of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide free base and acetone (25 mL, HPLC grade) under nitrogen. The suspension was stirred at 25° C. under nitrogen for 30 minutes to obtain a clear solution. To the mixture was added a 1.5 mL of 6 M hydrochloric acid (1.5 equiv) over 10 minutes. Within 5 minutes the solids came out. The slurry was stirred at 25° C. for 16 hours. The mixture was filtered under suction and solid was washed with acetone (10 mL). The drug substance was dried under vacuum at 55° C. for 16 hours to obtain 3.0 g of the hydrogen chloride salt (yield: 93%).
EXAMPLE 4
Table 1 below shows stability measured by degradation products (or assay) and appearance color. DPs are analyzed by HPLC (method see Table 3). They are calculated as area-% products. Compositions of the mixtures in mass % are as follows. Mixture 1: Lactose 200 mesh/maize starch modified 1500 LM/Aerosil 200/Magnesiumstearate 78.5:20:0.5:1 (m/m/m/m). Mixture 2: Mannitol/Avicel PH 102/Cutina HR (57:38:5) (m/m/m).
TABLE 1
Salt Form
Phosphate, Sulfate, Hydrochloride,
di mono mono
Test DP DP DP
Conditions [%] CL [%] CL [%] CL
Unstressed drug substance
Bulk 1.02 0.42 0.30
0.2% solutions or suspensions, 2 week 50° C.
pH 1 0.99 A ↓
pH 3 1.07 A ↓
pH 5 1.04 A ↓
pH 7 1.06 A ↓
pH 9 1.05 A ↓
pH 11 1.03 A ↓
Water 1.07 A ↓ 0.41 A ↓ 0.31 A ↓
Methanol 1.02 A * 0.68 A * 2.06 A *
Acetonitrile 1.93 A * 0.44 A * 0.38 A *
Acetonitrile/ 1.10 A * 0.80 A * 1.72 A *
Water
(50:50)
2% (or 5%) solutions or suspensions, 1 day room temperature
0.5% CMC A ↓ 0.45 A ↓ 0.33 A ↓
HPMC 1.04 A ↓ 0.47 A ↓ 0.32 A ↓
Cellulose
4000 0.5%
Tween 1.07 A ↓ 0.43 A ↓ 0.31 A ↓
80, 0.8%
Solid state, 2 week 50° C., tight container
Bulk 1.03 A 0.40 A 0.31 A
(HPLC)
Bulk No No No
(XRPD) change change change
Solid state, 2 week 80° C., tight container
Bulk 1.06 A 0.43 A 0.35 A
(HPLC)
Bulk No No No
(DSC) change change change
2 weeks 50° C., tight container
1% in mix- 0.96 A 0.41 A 0.27 A
ture 1
1% in mix- 1.11 A 0.44 A 0.39 A
ture 2
Solid state, 2 week 50° C./75% r.h.
Bulk 0.96 A 0.42 A 0.29 A
(HPLC)
Bulk Slightly No No
(XRPD) changed * change change
Solid state, 2 week 80° C./75% r.h.
Bulk 1.02 A 1.34 A 0.35 A
(HPLC)
Bulk Changed ** No No
(XRPD) change change
2 weeks 50° C./75% r.h.
1% in mix- 1.59 A 0.70 A 2.85 A
ture 1
1% in mix- 1.01 A 0.41 A 0.31 A
ture 2
Xenon light (approx. 1200 kLuxh)
Bulk 1.35 A 1.1 A 1.46 B
(HPLC)
Bulk No No No
(XRPD) change change change
Bulk corrosivity
2 day 80% No visible change No visible change No visible change
r.h. with in the surface of in the surface of in the surface of
stainless the stainless the stainless the stainless
steel coupon steel coupon steel coupon steel coupon
* T here is a new peak in the XRPD pattern when compared with the unstressed diphosphate.
** The XRPD pattern is similar to that of phosphate, yet with one extra peak.
↓ Suspension
* Clear solution after stress test
— Test not performed
A No change of color
B Slight discoloration
C Medium discoloration
D Strong discoloration
EXAMPLE 5
Table 2 below shows chemical and physico-chemical characteristics.
TABLE 2
Salt Form
Phosphate, Sulfate, Hydrochloride,
Parameter di mono mono
Elementary analysis calcul. found calcul. found calcul. found
% C 45.82 46.06 53.51 53.28 59.83 60.11
% H 4.73 5 4.84 4.91 5.21 5.06
% F 8.36 8.35 9.77 9.44 10.92 10.69
% N 6.17 6.08 7.2 7.08 8.05 7.88
% O 25.82 25.29 19.19 20.29 9.2 9.93
% P 9.09 9.22
% S 5.49 5.68 . .
% Cl 6.79 6.33
DSC-Purity
Heating rate 10° C./min N/A N/A N/A
HPLC-Purity (e.g. area-%)
1.02 0.42 0.30
Melting point (DSC)
Heating rate [° C./min] 10 10 10
Melting enthalpy (J/g) N/A N/A N/A
pH of 1% solution or suspension
In water 2.02 1.45 1.69
Solubility (approx. at 25° C., mg/ml)
0.1N HCL 0.004 (Final 0.003 (Final 0.002 (Final
pH 1.04) pH 1.09) pH 1.02)
Phosphate buffer, pH 6.8 0.001 (Final 0.002 (Final 0.000 (Final
pH 2.86) pH 1.82) pH 5.93)
Water 0.009 (Final 0.007 (Final 0.005 (Final
pH 1.94) pH 1.26) pH 1.67)
Methanol >40 24.4 >40
Ethanol 19.7 19.7 56.4
2-Propanol 14.3 4 10.3
Acetone 2.8 1.7 3.2
Ethyl Acetate 0.3 0.09 2.5
Acetonitrile 0.4 1.4 4.1
Thermogravimetry (weight loss in %)
Heating rate 10° C./min 0.19% at 150° C. 1.89% at 150° C. 0.48% at 150° C.
(%)
Residual solvents (%)
Heptane: Acetonitrile: Acetone:
0.0001463, 0.419087, 0.0002356,
Acetonitrile, Water: 1.36, Water: 0.4,.
Intrinsic dissolution rate (mg min−1 cm−2)
HCl 0.1N
Water
Water + Surfactant
(SDS)
NMR Chemical shift Chemical shift Chemical shift
changed changed changed
* Attempts to measure intrinsic dissolution rate were not successful due to low solubility.
EXAMPLE 6
Table 3 below shows morphic properties.
TABLE 3
Salt form
Phosphate, Sulfate, Hydrochloride,
Parameter di mono mono
Thermal properties
As is
DSC 213° C. N/A N/A
XRPD (crystallinity) Crystalline Crystalline Crystalline
After heating and cooling-
DSC N/A N/A N/A
XRPD N/A N/A N/A
Hygroscopicity
As is
Loss on drying by TGA 0.19 at 150° C. 1.89 at 150° C. 0.48 at 150° C.
(%)
DVS
Sorp. Desorp. Sorp. Desorp. Sorp. Desorp.
Weight Weight Weight Weight Weight Weight
RH (%) % chg. % chg. % chg. % chg. % chg. % chg.
 0.0 0.000 −0.038 0.000 1.007 −0.0001 −0.0114
25.0 0.059 0.136 1.232 1.256 0.3334 0.3799
50.0 0.149 0.341 1.455 1.495 0.4660 0.4932
75.0 0.270 1.268 1.634 1.716 0.5753 0.6069
85.0 0.400 1.828 1.835 0.6525 0.6817
95.0 3.420 3.420 2.330 2.330 0.8784 0.8784
XRPD after DVS test No change No change No change
Crystal modification after 72 hours vibration
DSC/XRPD/TG DSC/XRPD/TG DSC/XRPD/TG
Water XRPD pattern Dissociated to free Dissociated to free
changed, different base. base
than free base. Final pH 1.26 Final pH 1.94
Final pH 1.94
pH 6.8 buffer XRPD pattern Dissociated to free No form change
changed, different base Final pH 5.93
than free base. Final pH 1.82
Final pH 2.86
pH 3 buffer XRPD pattern Dissociated to free Dissociated to free
changed, different base base
than free base. Final pH 2.00 Final pH 2.89
Final pH 2.15
0.1N HCl solution XRPD pattern XRPD pattern XRPD pattern
changed, different changed, different changed, different
than free base. than that of free than that of free
base. base.
Methanol Y, crystalline to
crystalline
Ethanol XRPD pattern N, no form change N, no form change
changed, poorer
crystalline than the
original.
Iso Propanol N, no form change N, no form change N, no form change
Ethyl acetate N, no form change N, no form change N, no form change
Acetone N, no form change Y, crystalline to N, no form change
crystalline
Acetonitrile N, no form change N, no form change N, no form change
Effect of grinding
No change in No change in No change in
XRPD XRPD XRPD
Effect of compression
No change in No change in No change in
XRPD XRPD XRPD
N—no, Y—yes
EXAMPLE 7
Rat TK data of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide diphosphate dosed as a suspension, with a 10-fold increase in dose, showed a 3.1-fold increase in exposure from 10 to 100 mpk. The inter-subject exposure is slightly variable, especially at high dose (100 mpk). See Table 4.
TABLE 4
Dose AUC0-24/dose Cmax/dose
(mg/ AUC0-24 (ng*h/mL)/ Cmax (ng/mL)/ tmax
kg) Rat (ng*h/mL) (mg/kg/day) (ng/mL) (mg/kg/day) (h)
10 001 43300 4330 2820 282 8.00
002 52800 5280 3160 316 8.00
003 49400 4940 3100 310 4.00
100 004 232000 2320 14800 148 8.00
005 96800 968 4520 45.2 8.00
006 131000 1310 7490 74.9 8.00